Phase II Study to Compare Anti-VEGF Agents in Treatment of DME (12-EI-0134)

目的：糖尿病视网膜病变（DR）是导致视力损害的主要原因。DR的常见表现是糖尿病性黄斑水肿（DME），在过去几十年中，激光光凝是唯一被证实的治疗方法。研究表明，抗血管内皮生长因子（VEGF）注射剂（如贝伐单抗或雷珠单抗）可有效治疗DME患者。然而，目前还没有直接比较这些药物，以确定一种治疗方法是否比另一种更有效。本研究的目的是比较雷珠单抗与贝伐单抗治疗DME的疗效。研究人群：本随机研究将入组60例单眼或双眼继发于糖尿病的黄斑水肿和任何阶段DR（需要散射激光光凝治疗增殖性DR的受试者除外）的受试者。设计：在这项II期、比较性、双盲研究中，眼睛将被随机分配接受雷珠单抗或贝伐单抗。在研究的初始阶段，参与者将参加一项为期三个阶段、36周的交叉研究，其中研究眼睛将被分配到四个治疗组之一（即，处理序列）。两种药物和三个阶段形成如下的AAB/ABB/BBA/BAA模式：第1组眼睛将在基线和第4、8、12、16和20周接受一系列雷珠单抗的玻璃体内注射，然后在第24、28和32周交叉接受一系列贝伐单抗的玻璃体内注射。第2组眼睛将在基线和第4周和第8周接受一系列雷珠单抗的玻璃体内注射，然后在第12周、第16周、第20周、第24周、第28周和第32周交叉接受一系列贝伐单抗的玻璃体内注射。第3组眼睛将在基线和第4、8、12、16和20周接受一系列贝伐珠单抗玻璃体内注射，然后在第24、28和32周交叉接受一系列雷珠单抗玻璃体内注射。第4组眼睛将在基线和第4周和第8周接受一系列贝伐珠单抗的玻璃体内注射，然后在第12、16、20、24、28和32周交叉接受一系列雷珠单抗的玻璃体内注射。一只眼睛入组本研究的受试者将随机将这只眼睛分配至上述四组之一。双眼入组研究的受试者将右眼随机分配至上述四组之一。对于右眼随机分配至组1或组2的受试者，左眼将随机分配至组3或组4;相反，对于右眼随机分配至组3或组4的受试者，左眼将随机分配至组1或组2。在该交叉期后，眼睛将返回到最初分配的治疗（雷珠单抗或贝伐珠单抗），并根据需要进行治疗，直至最后一名入组受试者入组后3年的共同终止日期。治疗研究者和受试者均对分组设盲。将在第12、24、36周以及第1、2和3年评估主要结局。结果测量：主要结果测量是最佳矫正视力（BCVA）的平均变化。BCVA从基线到三个阶段中的每个阶段结束后四周的变化（即，第12、24和36周）以及第1、2和3年的数据将用于主要分析。次要结局（在基线和第12周访视、第12周和第24周访视、第24周和第36周访视之间以及在第1年、第2年和第3年评估）将包括通过OCT测量的治疗组的中央黄斑厚度和中央视网膜体积的平均变化; BCVA、中央黄斑厚度和视网膜体积的变化的斜率;视力改善大于或等于10个字母的眼睛比例;视力改善大于或等于15个字母的眼睛比例; logOCT损失或增益大于或等于0.1 log单位的眼睛比例; logOCT中损失或增加大于或等于0.05 log单位的眼睛的比例;荧光素血管造影术所证实的黄斑中液体渗漏的变化;以及黄斑结构改善的变化（即，其他次要结果将包括符合显著恶化、治疗成功或治疗失败标准的眼睛的比例，在研究的按需治疗阶段中眼睛中重新注射的频率，以及在研究过程中接受局灶/格栅激光光凝或其他辅助治疗的眼睛的比例。安全性结局包括不良事件的数量和严重程度。由于视力丧失或不良事件而退出试验用产品的眼睛数量以及被认为疾病恶化的眼睛数量也将有助于安全性评估。 五十六例受试者入组研究，入组于2014年1月关闭。 所有参与者将在2014年10月前完成为期36周的交叉试验阶段。

Objective: Diabetic retinopathy (DR) remains a leading cause of visual impairment. A frequent manifestation of DR is diabetic macular edema (DME) for which laser photocoagulation has been the only proven treatment for the last several decades. Studies have shown that anti-vascular endothelial growth factor (VEGF) injections such as bevacizumab or ranibizumab have been efficacious in treating patients with DME. However, there has been no direct comparison of these agents to determine whether one treatment is more effective than the other. The objective of this study is to compare the treatment efficacy of ranibizumab versus bevacizumab in eyes with DME. Study Population: Sixty (60) participants with macular edema secondary to diabetes and any stage of DR (other than those requiring scatter laser photocoagulation for proliferative DR) in one or both eyes will be enrolled in this randomized study. Design: In this Phase II, comparative, double-masked study, eyes will be randomly assigned to receive ranibizumab or bevacizumab. During the initial phase of the study participants will participate in a three-period, 36-week, cross-over study in which study eyes will be assigned to one of four treatment groups (i.e., treatment sequences). The two drugs and three periods form an AAB/ABB/BBA/BAA pattern as follows: Group 1 eyes will receive a series of intravitreal injections of ranibizumab at baseline and Weeks 4, 8, 12, 16 and 20, then cross-over to receive a series of intravitreal injections of bevacizumab at Weeks 24, 28 and 32. Group 2 eyes will receive a series of intravitreal injections of ranibizumab at baseline and Weeks 4 and 8, then cross-over to receive a series of intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32. Group 3 eyes will receive a series of intravitreal injections of bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20, then cross-over to receive a series of intravitreal injections of ranibizumab at Weeks 24, 28 and 32. Group 4 eyes will receive a series of intravitreal injections of bevacizumab at baseline and Weeks 4 and 8, then cross-over to receive a series of intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32. Participants for whom one eye is enrolled in the study will have this eye randomized to one of the four groups above. Participants for whom both eyes are enrolled in the study will have the right eye randomized to one of the four groups above. For those whose right eye is randomized to Group 1 or 2, the left eye will be randomized to Group 3 or 4; conversely, for those whose right eye is randomized to Group 3 or 4, the left eye will be randomized to Group 1 or 2. Following this cross-over phase, eyes will be returned to the treatment (ranibizumab or bevacizumab) to which they were originally assigned and treated on an as-needed basis through a common termination date three years from enrollment of the last-enrolled participant. Both the treating investigators and participants will be masked to the group assignments. The primary outcome will be assessed at Weeks 12, 24, 36 and at Years 1, 2 and 3. Outcome Measures: The primary outcome measure is the mean change in best-corrected visual acuity (BCVA). Changes in BCVA from baseline to four weeks following the end of each of the three periods (i.e., Weeks 12, 24 and 36) and at Years 1, 2 and 3 will be used for the primary analysis. Secondary outcomes (assessed between the baseline and Week 12 visits, Weeks 12 and 24 visits and Weeks 24 and 36 visits and at Years 1, 2 and 3) will include the mean changes in central macular thickness and central retinal volume by treatment group as measured by OCT; the slope of the changes in BCVA, central macular thickness and retinal volume; the proportion of eyes with visual improvement greater than or equal to 10 letters; the proportion of eyes with visual improvement greater than or equal to 15 letters; the proportion of eyes with greater than or equal to 0.1 log unit loss or gain in logOCT; the proportion of eyes with greater than or equal to 0.05 log unit loss or gain in logOCT; changes in fluid leakage in the macula as demonstrated by fluorescein angiography; and changes in macular structural improvement (i.e., resolution of cystic changes) as measured by OCT. Other secondary outcomes will include the proportion of eyes meeting criteria for significant worsening, treatment success, or treatment failure, the frequency of re-injection among eyes in the treatment-as-needed phase of the study, and the proportion of eyes receiving focal/grid laser photocoagulation or other adjuvant treatment during the course of the study. Safety outcomes include the number and severity of adverse events. The number of eyes withdrawn from the investigational product due to vision loss or adverse events and the number of eyes deemed to have worsening disease will also contribute to the assessment of safety. Fifty-six (56) participants have been enrolled in the study and enrollment was closed in January 2014. All participants will complete the 36-week crossover phase of the trial by October 2014.